This competitive renewal application outlines our plans to to map and eventually identify the susceptibility genes for human systemic lupus erythematosus. During the first funding period, we have successfully recruited over 250 SLE sib-pair and multiplex families, as well as 130 trio (affected SLE patient with both parents) families. Genome-wide marker screens have been performed in these Minnesota pedigrees, and several chromosomal regions that appear likely to harbor SLE susceptibility genes have been identified. Dense microsatellite marker mapping has been initiated in several chromosomal regions that show the most convincing evidence for linkage in our family collection (1q41, 6p21 (HLA), 16q21, 20q, and 20p). More recently, we have begun to analyze several candidate genes in these regions. Our collection of SLE families is one of the largest in the world, and we are well poised to move this project forward in the next funding period. In the next five years we propose to continue collection additional SLE sib-pair and trio families, with a goal of recruiting 125 sib-pair families and 300 trios. In addition we will collect a group of 200 age-, sex- and ethnicity-matched control individuals for case/control association studies with the accumulated marker data. We will further refine the location of the susceptibility loci within the HLA region using the recombinant ancestral haplotype approach, and then attempt to identify the sequence variations within the HLA that confer risk for SLE. Finally, we will continue fine mapping in the non-HLA chromosomal regions that show linkage to the lupus phenotype. Within the time frame of the next five years we hope to begin identifying the disease-associated sequence polymorphisms that confer risk for human SLE. The identification of the lupus genes will be critically important for furthering our understanding of this disease, and for rationally targeting new therapies.